Annual review of pharmacology and toxicology
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Annu. Rev. Pharmacol. Toxicol. · Jan 2015
ReviewDREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility.
In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). ⋯ We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.
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Annu. Rev. Pharmacol. Toxicol. · Jan 2015
ReviewCalcitonin gene-related peptide (CGRP): a new target for migraine.
Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. ⋯ This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.
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Annu. Rev. Pharmacol. Toxicol. · Jan 2015
ReviewImproving postapproval drug safety surveillance: getting better information sooner.
Adverse drug events (ADEs) are an important public health concern, accounting for 5% of all hospital admissions and two-thirds of all complications occurring shortly after hospital discharge. There are often long delays between when a drug is approved and when serious ADEs are identified. Recent and ongoing advances in drug safety surveillance include the establishment of government-sponsored networks of population databases, the use of data mining approaches, and the formal integration of diverse sources of drug safety information. These advances promise to reduce delays in identifying drug-related risks and in providing reassurance about the absence of such risks.
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Annu. Rev. Pharmacol. Toxicol. · Jan 2015
ReviewDrug disposition in obesity: toward evidence-based dosing.
Obesity and morbid obesity are associated with many physiological changes affecting pharmacokinetics, such as increased blood volume, cardiac output, splanchnic blood flow, and hepatic blood flow. In obesity, drug absorption appears unaltered, although recent evidence suggests that this conclusion may be premature. ⋯ For obese children, we propose two methods to distinguish between developmental and obesity-related changes. Future research should focus on the characterization of physiological concepts to predict the optimal dose for each drug in the obese population.